Mechanism of Retinal Neovascularization in OIR: Role of ACAT-1

Abstract

According to the National Eye Institute, Retinopathy of Prematurity (ROP) is the leading cause of vision loss in childhood. About 400–600 infants each year in the US become legally blind from ROP (NIH, 2019). ROP primarily affects premature infants weighing less than 2.75 pounds who are born before thirty-one weeks of gestation (NIH, 2019). Today, with the advances being made in neonatal intensive care, smaller premature infants are being saved. Because these infants are at a much higher risk for ROP, it has become increasingly important to understand ROP. ROP affects the blood vessels in the retina, which is the thin layer of tissue that lines the back of the eye and is responsible for receiving light and converting it into neural signals. Loss of vision occurs when abnormal blood vessels grow and spread throughout the retina and into the vitreous, developing neovascular tufts, causing hemorrhage. Retinal detachment is the main cause of visual impairment and blindness in ROP (NIH, 2019). The primary current treatments are laser therapy and anti-vascular endothelial growth factor (VEGF), but these therapies have shown negative side effects and complications associated with them being invasive procedures such as intraocular swelling, retinal detachment and infectious endophthalmitis (Dowler, 2003). The mechanism behind retinopathy of prematurity is unclear, however; macrophage proliferation has been found to have a critical role in the development of retinal neovascularization by secreting growth factors and inflammatory cytokines such as VEGF, Interleukin 6 (IL-6), Monocyte colony stimulating factor (MCSF) and trigger receptor expressed on myeloid cells (TREM-1) (Zhou, et al. 2017). The manner in which macrophages are activated for this process is also unknown, however; lipid metabolism is vital for maintaining macrophage homeostasis and function. Lipid loading in macrophages increases intracellular cholesterol esters (CEs), which induce an inflammatory phenotype. Acyl coenzyme A: cholesterol acyltransferase-1 (ACAT-1) is an enzyme localized in macrophage endoplasmic reticulum that is responsible for cholesterol esterification with fatty acids and the formation of CEs. Our preliminary results in wild-type (WT) mice pups treated with intraperitoneal injections (I.P.) of ACAT-1 inhibitor in a model of oxygen-induced retinopathy show significant decrease of retinal neovascularization, avascular area and expression of TREM-1, M-CSF and VEGF. We hypothesize that ACAT-1 activityderived high cholesterol levels in macrophages during hypoxia induce retinal neovascularization.